Lee Michelle J, Koff Jean L, Switchenko Jeffrey M, Jhaney C Ileen, Harkins R Andrew, Patel Sharvil P, Dave Sandeep S, Flowers Christopher R
Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Medicine, Morehouse School of Medicine, Atlanta, Georgia, USA.
Cancer. 2020 Aug 1;126(15):3493-3503. doi: 10.1002/cncr.32866. Epub 2020 May 29.
Significant racial differences have been observed in the incidence and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) in the United States, but to the authors' knowledge it remains unclear whether genomic differences contribute to these disparities.
To understand the influences of genetic ancestry on tumor genomic alterations, the authors estimated the genetic ancestry of 1001 previously described patients with DLBCL using unsupervised model-based Admixture global ancestry analysis applied to exome sequencing data and examined the mutational profile of 150 DLBCL driver genes in tumors obtained from this cohort.
Global ancestry prediction identified 619 patients with >90% European ancestry, 81 patients with >90% African ancestry, and 50 patients with >90% Asian ancestry. Compared with patients with DLBCL with European ancestry, patients with African ancestry were aged >10 years younger at the time of diagnosis and were more likely to present with B symptoms, elevated serum lactate dehydrogenase, extranodal disease, and advanced stage disease. Patients with African ancestry demonstrated worse overall survival compared with patients with European ancestry (median, 4.9 years vs 8.8 years; P = .04). Recurrent mutations of MLL2 (KMT2D), HIST1H1E, MYD88, BCL2, and PIM1 were found across all ancestry groups, suggesting shared mechanisms underlying tumor biology. The authors also identified 6 DLBCL driver genes that were more commonly mutated in patients with African ancestry compared with patients with European ancestry: ATM (21.0% vs 7.75%; P < .001), MGA (19.7% vs 5.33%; P < .001), SETD2 (17.3% vs 5.17%; P < .001), TET2 (12.3% vs 5.82%; P = .029), MLL3 (KMT2C) (11.1% vs 4.36%; P = .013), and DNMT3A (11.1% vs 4.52%; P = .016).
Distinct prevalence and patterns of mutation highlight an important difference in the mutational landscapes of DLBCL arising in different ancestry groups. To the authors' knowledge, the results of the current study provide the first-ever characterization of genetic alterations among patients with African descent who are diagnosed with DLBCL.
在美国，弥漫性大B细胞淋巴瘤（DLBCL）的发病率和临床结局存在显著的种族差异，但据作者所知，尚不清楚基因组差异是否导致了这些差异。
为了解遗传血统对肿瘤基因组改变的影响，作者使用基于无监督模型的混合全球血统分析方法，对1001例先前描述的DLBCL患者的外显子测序数据进行分析，估计其遗传血统，并检查该队列中肿瘤样本中150个DLBCL驱动基因的突变谱。
全球血统预测确定了619例欧洲血统占比>90%的患者、81例非洲血统占比>90%的患者和50例亚洲血统占比>90%的患者。与欧洲血统的DLBCL患者相比，非洲血统的患者诊断时年龄小>10岁，更有可能出现B症状、血清乳酸脱氢酶升高、结外病变和晚期疾病。与欧洲血统的患者相比，非洲血统的患者总生存期更差（中位数分别为4.9年和8.8年；P = .04）。在所有血统组中均发现了MLL2（KMT2D）、HIST1H1E、MYD88、BCL2和PIM1的复发性突变，表明肿瘤生物学存在共同机制。作者还鉴定出6个DLBCL驱动基因，与欧洲血统的患者相比，非洲血统的患者中这些基因发生突变的情况更为常见：ATM（21.0%对7.75%；P < .001）、MGA（19.7%对5.33%；P < .001）、SETD2（17.3%对5.17%；P < .001）、TET2（12.3%对5.82%；P = .029）、MLL3（KMT2C）（11.1%对4.36%；P = .013）和DNMT3A（11.1%对4.52%；P = .016）。
不同的突变发生率和模式凸显了不同血统组中DLBCL突变图谱的重要差异。据作者所知，本研究结果首次描述了被诊断为DLBCL的非洲裔患者的基因改变情况。
